Protein kinases are a class of proteins (enzymes) that regulate a variety of cellular functions. This is accomplished by the phosphorylation of specific amino acids on protein substrates resulting in conformational alteration of the substrate protein. The conformational change modulates the activity of the substrate or its ability to interact with other binding partners. The enzyme activity of the protein kinase refers to the rate at which the kinase adds phosphate groups to a substrate. It can be measured, for example, by determining the amount of a substrate that is converted to a product as a function of time. Phosphorylation of a substrate occurs at the active-site of a protein kinase.
Tyrosine kinases are a subset of protein kinases that catalyze the transfer of the terminal phosphate of adenosine triphosphate (ATP) to tyrosine residues on protein substrates. These kinases play an important part in the propagation of growth factor signal transduction that leads to cellular proliferation, differentiation and migration.
For example, fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) have been recognized as important mediators of tumor promoted angiogenesis. VEGF activates endothelial cells by signaling through two high affinity receptors, one of which is the kinase insert domain-containing receptor (KDR). See, Hennequin L. F. et. al., J. Med. Chem. 2002, 45(6), pp 1300. FGF activates endothelial cells by signaling through the FGF receptor (FGFR). Solid tumors depend upon the formation of new blood vessels (angiogenesis) to grow. Accordingly, inhibitors of the receptors FGFR and KDR that interfere with the growth signal transduction, and thus slow down or prevent angiogenesis, are useful agents in the prevention and treatment of solid tumors. See, Klohs W. E. et. al., Current Opinion in Biotechnology 1999, 10, p. 544.
There are several examples of small molecule inhibitors of protein kinase catalytic activity. In particular, small molecule inhibitors typically block the phosphorylation of substrates by tightly interacting with the protein kinase ATP binding site (or “active site”). See, WO 98/24432 and Hennequin L. F. et. al., J. Med. Chem. 2002, 45(6), pp 1300. Several of these compounds inhibit multiple targets. For example, WO 99/61444 (Warner-Lambert) discloses bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines of formula
that are asserted to inhibit cyclin dependent kinases Cdk1, Cdk2 and Cdk4 as well as the growth factor receptor tyrosine kinase enzymes PDGFR and FGFR. Some compounds are also asserted to inhibit Cdk6.
WO 01/55148A1 discloses a method for treating neurodegenerative diseases in mammals comprising administering an effective amount of a cyclin-dependent kinase inhibitors, preferably using Cdk inhibitors of formula

U.S. Pat. No. 6,150,373 discloses bicyclic nitrogen heterocycles of formula
that are stated to inhibit the T-cell tyrosine kinase p56lck.
WO 02/18380 A1 discloses 7-oxo pyridopyrimidines of formula
that are stated to inhibit p38 mediated cellular functions and are thus inhibitors of cellular proliferation.
WO 96/34867 discloses 6-aryl pyrido[2,3-d]pyrimidine 7-imines, 7-ones, and 7-thiones of formula
are inhibitors of protein kinases, and useful in treating cellular proliferation mediated diseases.
WO 98/33798 discloses pyrido[2,3-d]pyrimidines and 4-aminopyrimidines as inhibitors of cellular proliferation. Specifically, this publication discloses a group of 7,8-dihydro-2-(amino and thio)pyrido[2,3-d]pyrimidines and 2,4-diaminopyrimidines that are potent inhibitors of cyclin-dependent kinases (Cdks) and growth mediated kinases.
WO 01/64679 A1 discloses 1,5-disubstituted-3,4-dihydro-1H-pyrimido[4,5-D]pyrimidin-2-one compounds of formula
that are stated to be useful in treating CSBP/P38 kinase mediated diseases.
WO 02/12237 A2 discloses a process for preparing 2-(4-pyridyl)amino-6-dialkoxyphenyl-pyrido[2,3-d]pyrimidin-7-ones, and WO 02/12238 A2 discloses 2-(4-pyridyl)amino-6-dialkoxyphenyl-pyrido[2,3-d]pyrimidin-7-ones of formula (I).

These compounds are asserted to be useful in treating diseases resulting from uncontrolled cell growth.
There continues to be a need for easily synthesized, small-molecule compounds effective in inhibiting the catalytic activity of protein kinases, in particular FGFR and KDR kinases for treating one or more types of solid tumors. It is particularly desirable to provide small molecule inhibitors that are selective for FGFR and KDR. This is desirable because the potential concomitant inhibition of targets involved in angiogenesis could provide better efficacy. On the other hand, toxicity and other undesirable complications may follow from inhibiting multiple targets. It is preferable that such small molecule inhibitors also possess advantageous bioavailability profiles. It is therefore desirable to provide such compounds and pharmaceutical compositions containing these compounds.